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Andréen, Lotta
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Publications (9 of 9) Show all publications
Bäckström, T., Haage, D., Löfgren, M., Johansson, I. M., Strömberg, J., Nyberg, S., . . . Bengtsson, S. K. (2011). Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons. Neuroscience, 191(Special issue), 46-54.
Open this publication in new window or tab >>Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons
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2011 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 191, no Special issue, 46-54 p.Article, review/survey (Refereed) Published
Abstract [en]

Some women have negative mood symptoms, caused by progestagens in hormonal contraceptives or sequential hormone therapy or by progesterone in the luteal phase of the menstrual cycle, which may be attributed to metabolites acting on the GABA-A receptor. The GABA system is the major inhibitory system in the adult CNS and most positive modulators of the GABA-A receptor (benzodiazepines, barbiturates, alcohol, GABA steroids), induce inhibitory (e.g. anesthetic, sedative, anticonvulsant, anxiolytic) effects. However, some individuals have adverse effects (seizures, increased pain, anxiety, irritability, aggression) upon exposure. Positive GABA-A receptor modulators induce strong paradoxical effects including negative mood in 3%-8% of those exposed, while up to 25% have moderate symptoms. The effect is biphasic: low concentrations induce an adverse anxiogenic effect while higher concentrations decrease this effect and show inhibitory, calming properties. The prevalence of premenstrual dysphoric disorder (PMDD) is also 3%-8% among women in fertile ages, and up to 25% have more moderate symptoms of premenstrual syndrome (PMS). Patients with PMDD have severe luteal phase-related symptoms and show changes in GABA-A receptor sensitivity and GABA concentrations. Findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor, which may be explained by one or more of three hypotheses regarding the paradoxical effect of GABA steroids on behavior: (1) under certain conditions, such as puberty, the relative fraction of certain GABA-A receptor subtypes may be altered, and at those subtypes the GABA steroids may act as negative modulators in contrast to their usual role as positive modulators; (2) in certain brain areas of vulnerable women the transmembrane C1(-) gradient may be altered by factors such as estrogens that favor excitability; (3) inhibition of inhibitory neurons may promote disinhibition, and hence excitability. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain. (C) 2011 Published by Elsevier Ltd on behalf of IBRO.

Place, publisher, year, edition, pages
Oxford: , 2011
Keyword
premenstrual syndrome, GABA-A receptor, paradoxical, GABA-steroid, neurosteroid
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-49248 (URN)10.1016/j.neuroscience.2011.03.061 (DOI)000295749300006 ()
Available from: 2011-11-09 Created: 2011-11-04 Last updated: 2018-01-12Bibliographically approved
Turkmen, S., Bäckström, T., Wahlström, G., Andréen, L. & Johansson, I.-M. (2011). Tolerance to allopregnanolone with focus on the GABA-A receptor. British Journal of Pharmacology, 162(2), 311-327.
Open this publication in new window or tab >>Tolerance to allopregnanolone with focus on the GABA-A receptor
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2011 (English)In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 162, no 2, 311-327 p.Article in journal (Refereed) Published
Abstract [en]

Many studies have suggested a relationship between stress, sex steroids, and negative mental and mood changes in humans. The progesterone metabolite allopregnanolone is a potent endogenous ligand of the γ-amino butyric acid -A (GABA-A) receptor, and the most discussed neuroactive steroid. Variations in the levels of neuroactive steroids that influence the activity of the GABA-A receptor cause a vulnerability to mental and emotional pathology. There are physiological conditions in which allopregnanolone production increases acutely (e.g. stress) or chronically (e.g. menstrual cycle, pregnancy), thus exposing the GABA-A receptor to high and continuous allopregnanolone concentrations. In such conditions, tolerance to allopregnanolone may develop. We have shown that both acute and chronic tolerances can develop to the effects of allopregnanolone. Following the development of acute allopregnanolone tolerance, there is a decrease in the abundance of the GABA-A receptor α4 subunit and the expression of the α4 subunit mRNA in the ventral-posteriomedial (VPM) nucleus of the thalamus. Little is known about the mechanism behind allopregnanolone tolerance and its effects on assembly of the GABA-A receptor composition. The exact mechanism of the allopregnanolone tolerance phenomena remains unclear. The purpose of this review is to summarize certain aspects of current knowledge concerning allopregnanolone tolerance and changes in the GABA-A receptors.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2011
Keyword
Allopregnanolone, GABA-A receptor, tolerance, silent second, mRNA, neurosteroid
National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-36798 (URN)10.1111/j.1476-5381.2010.01059.x (DOI)000285305900001 ()20883478 (PubMedID)
Available from: 2010-10-12 Created: 2010-10-12 Last updated: 2018-01-12Bibliographically approved
Andréen, L., Nyberg, S., Turkmen, S., van Wingen, G., Fernández, G. & Bäckström, T. (2009). Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators. Psychoneuroendocrinology, 34(8), 1121-1132.
Open this publication in new window or tab >>Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators
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2009 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 34, no 8, 1121-1132 p.Article in journal (Refereed) Published
Abstract [en]

Certain women experience negative mood symptoms as a result of progesterone during the luteal phase of the menstrual cycle, progestagens in hormonal contraceptives, or the addition of progesterone or progestagens in sequential hormone therapy (HT). This phenomenon is believed to be mediated via the action of the progesterone metabolites on the GABA(A) system, which is the major inhibitory system in the mammalian CNS. The positive modulators of the GABA(A) receptor include allopregnanolone and pregnanolone, both neuroactive metabolites of progesterone, as well as benzodiazepines, barbiturates, and alcohol. Studies on the effect of GABA(A) receptor modulators have shown contradictory results; although human and animal studies have revealed beneficial properties such as anaesthesia, sedation, anticonvulsant effects, and anxiolytic effects, recent reports have also indicated adverse effects such as anxiety, irritability, and aggression. It has actually been suggested that several GABA(A) receptor modulators, including allopregnanolone, have biphasic effects, in that low concentrations increase an adverse, anxiogenic effect whereas higher concentrations decrease this effect and show beneficial, calming properties. The allopregnanolone increase during the luteal phase in fertile women, as well as during the addition of progesterone in HT, has been shown to induce adverse mood in women. The severity of these mood symptoms is related to the allopregnanolone serum concentrations in a manner similar to an inverted U-shaped curve. Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to endogenous luteal phase levels, while low and high concentrations have less effect on mood. It has also been shown that progesterone/allopregnanolone treatment in women increases the activity in the amygdala (as measured with functional magnetic resonance imaging) in a similar way to the changes seen during anxiety reactions. However, it is evident that only certain women experience adverse mood during progesterone or GABA(A) receptor modulator treatments. Women with premenstrual dysphoric disorder (PMDD) have severe luteal phase related symptoms; in this phase, they show changes in GABA(A) receptor sensitivity and GABA concentrations that are related to the severity of the condition. These findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA(A) receptor. CONCLUSION: Progesterone and progestagens induce negative mood, most probably via their GABA(A) receptor active metabolites. In postmenopausal women treated with progesterone and animals treated with allopregnanolone, there is a bimodal association between serum allopregnanolone concentration and adverse mood, resembling an inverted U-shaped curve. In humans, the maximal effective concentration of allopregnanolone for producing negative mood is within the range of physiological luteal phase serum concentrations.

Keyword
GABAA receptor; Allopregnanolone; Negative mood; PMDD; Hormone therapy; Bimodal
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-36805 (URN)10.1016/j.psyneuen.2009.02.003 (DOI)19272715 (PubMedID)
Available from: 2010-10-12 Created: 2010-10-12 Last updated: 2017-12-12Bibliographically approved
Andréen, L., Sundström-Poromaa, I., Bixo, M., Nyberg, S. & Bäckström, T. (2006). Allopregnanolone concentration and mood: a bimodal association in postmenopausal women treated with oral progesterone.. Psychopharmacology, 187(2), 209-221.
Open this publication in new window or tab >>Allopregnanolone concentration and mood: a bimodal association in postmenopausal women treated with oral progesterone.
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2006 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 187, no 2, 209-221 p.Article in journal (Refereed) Published
Keyword
Administration; Oral, Affect/*drug effects, Climacteric/*drug effects, Cross-Over Studies, Dose-Response Relationship; Drug, Double-Blind Method, Drug Administration Schedule, Drug Therapy; Combination, Estradiol/analogs & derivatives/pharmacology, Female, Hormone Replacement Therapy, Humans, Medroxyprogesterone 17-Acetate/blood/*pharmacology, Middle Aged, Pregnanolone/*blood
Identifiers
urn:nbn:se:umu:diva-16547 (URN)10.1007/s00213-006-0417-0 (DOI)16724185 (PubMedID)
Available from: 2007-10-05 Created: 2007-10-05 Last updated: 2017-12-14Bibliographically approved
Andréen, L., Spigset, O., Andersson, A., Nyberg, S. & Bäckström, T. (2006). Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone.. Maturitas, 54(3), 238-244.
Open this publication in new window or tab >>Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone.
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2006 (English)In: Maturitas, ISSN 0378-5122, E-ISSN 1873-4111, Vol. 54, no 3, 238-244 p.Article in journal (Refereed) Published
Keyword
Administration; Oral, Adult, Aged, Area Under Curve, Estrogen Replacement Therapy, Female, Humans, Middle Aged, Postmenopause, Pregnanolone/administration & dosage/blood/pharmacokinetics, Progesterone/administration & dosage/blood/*pharmacokinetics
Identifiers
urn:nbn:se:umu:diva-10381 (URN)10.1016/j.maturitas.2005.11.005 (DOI)16406399 (PubMedID)
Available from: 2008-09-02 Created: 2008-09-02 Last updated: 2017-12-14Bibliographically approved
Andréen, L., Sundström-Poromaa, I., Bixo, M., Andersson, A., Nyberg, S. & Bäckström, T. (2005). Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone.. Psychoneuroendocrinology, 30(2), 212-224.
Open this publication in new window or tab >>Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone.
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2005 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 30, no 2, 212-224 p.Article in journal (Refereed) Published
Keyword
Administration; Intravaginal, Adult, Affect/physiology, Cross-Over Studies, Dose-Response Relationship; Drug, Double-Blind Method, Drug Therapy; Combination, Estradiol/administration & dosage, Female, Hormone Replacement Therapy/*adverse effects/psychology, Humans, Middle Aged, Mood Disorders/blood/*chemically induced, Postmenopause/blood/*drug effects/psychology, Pregnanolone/*administration & dosage/*adverse effects/blood, Progesterone/*administration & dosage/adverse effects/blood, Severity of Illness Index
Identifiers
urn:nbn:se:umu:diva-16940 (URN)10.1016/j.psyneuen.2004.07.003 (DOI)15471618 (PubMedID)
Available from: 2007-10-22 Created: 2007-10-22 Last updated: 2017-12-14Bibliographically approved
Bäckström, T., Andersson, A., Andreén, L., Birzniece, V., Bixo, M., Björn, I., . . . Zingmark, E. (2003). Pathogenesis in menstrual cycle-linked CNS disorders.. Annals of the New York Academy of Sciences, 1007, 42-53.
Open this publication in new window or tab >>Pathogenesis in menstrual cycle-linked CNS disorders.
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2003 (English)In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1007, 42-53 p.Article, review/survey (Other academic) Published
Keyword
Affect/physiology, Animals, Female, Humans, Menstrual Cycle/*physiology, Mood Disorders/*etiology/physiopathology/psychology, Pregnanolone/physiology, Premenstrual Syndrome/*etiology/physiopathology/psychology, Receptors; GABA-A/physiology
Identifiers
urn:nbn:se:umu:diva-16450 (URN)10.1196/annals.1286.005 (DOI)14993039 (PubMedID)
Available from: 2007-09-28 Created: 2007-09-28 Last updated: 2017-12-14Bibliographically approved
Andréen, L., Bixo, M., Nyberg, S., Sundström-Poromaa, I. & Bäckström, T. (2003). Progesterone effects during sequential hormone replacement therapy. European Journal of Endocrinology, 148(5), 571-577.
Open this publication in new window or tab >>Progesterone effects during sequential hormone replacement therapy
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2003 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 148, no 5, 571-577 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-5130 (URN)12720542 (PubMedID)
Available from: 2006-05-03 Created: 2006-05-03 Last updated: 2017-12-14Bibliographically approved
Bäckström, T., Andreen, L., Birzniece, V., Björn, I., Johansson, I.-M., Nordenstam-Haghjo, M., . . . Zhu, D. (2003). The role of hormones and hormonal treatments in premenstrual syndrome. CNS Drugs, 17(5), 325-342.
Open this publication in new window or tab >>The role of hormones and hormonal treatments in premenstrual syndrome
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2003 (English)In: CNS Drugs, ISSN 1172-7047, E-ISSN 1179-1934, Vol. 17, no 5, 325-342 p.Article in journal (Refereed) Published
Abstract [en]

Premenstrual syndrome (PMS) is a menstrual cycle-linked condition with both mental and physical symptoms. Most women of fertile age experience cyclical changes but consider them normal and not requiring treatment. Up to 30% of women feel a need for treatment. The aetiology is still unclear, but sex steroids produced by the corpus luteum of the ovary are thought to be symptom provoking, as the cyclicity disappears in anovulatory cycles when a corpus luteum is not formed. Progestogens and progesterone together with estrogen are able to induce similar symptoms as seen in PMS. Symptom severity is sensitive to the dosage of estrogen. The response systems within the brain known to be involved in PMS symptoms are the serotonin and GABA systems. Progesterone metabolites, especially allopregnanolone, are neuroactive, acting via the GABA system in the brain. Allopregnanolone has similar effects as benzodiazepines, barbiturates and alcohol; all these substances are known to induce adverse mood effects at low dosages in humans and animals. SSRIs and substances inhibiting ovulation, such as gonadotrophin-releasing hormone (GnRH) agonists, have proven to be effective treatments. To avoid adverse effects when high dosages of GnRH agonists are used, add-back hormone replacement therapy is recommended. Spironolactone also has a beneficial effect, although not as much as SSRIs and GnRH agonists.

Keyword
Premenstrual syndrome, Serotonin reuptake inhibitors, therapeutic use, Gonadotropin releasing hormone agonists, therapeutic use, Surgery, Oral contraceptives, therapeutic use, Spironolactone, therapeutic use, Progesterone, therapeutic use, Hormones, therapeutic use
Identifiers
urn:nbn:se:umu:diva-37054 (URN)12665391 (PubMedID)
Available from: 2010-10-19 Created: 2010-10-19 Last updated: 2017-12-12Bibliographically approved
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